CN1220693C - Process for preparation of 3-sulfonyloxy-3-cephem compounds - Google Patents
Process for preparation of 3-sulfonyloxy-3-cephem compounds Download PDFInfo
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- CN1220693C CN1220693C CNB008020035A CN00802003A CN1220693C CN 1220693 C CN1220693 C CN 1220693C CN B008020035 A CNB008020035 A CN B008020035A CN 00802003 A CN00802003 A CN 00802003A CN 1220693 C CN1220693 C CN 1220693C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The present invention provides a process for the preparation of 3-sulfonyloxy-3-cephem compounds of general formula (3), characterized by reacting a 3-hydroxy-3-cephem compound of general formula (1) with a sulfonic acid halide of general formula (2) in an organic solvent in the presence of an alkali metal carbonate or an alkaline earth metal carbonate wherein R<1> to R<4> and X are each as defined in the description.
Description
Technical field
The present invention relates to the preparation method of 3-sulfonyloxy-3-cephem compounds.
The 3-sulfonyloxy-3-cephem compounds is for example common widely used oral antibiotic Ceftibuten (ceftibuten) (up-to-date antibiotics guide the 9th edition, wine well gram is controlled work, the important synthetic intermediate of effective antimicrobial drug of has a broad antifungal spectrum such as the 85th page, 1994).
Background technology
As the preparation method of the 3-sulfonyloxy-3-cephem compounds of formula (3) expression, general method is that sulfonic acid halide or sulphonic acid anhydride and 3-hydroxyl-3-Cephem Derivative are reacted, and deriving obtains the 3-sulfonyloxy-3-cephem compounds.
But, as J.Org.Chem.,
54, 4962 (1989) records like that, use R
4During for the sulfonic acid halide of the formula (2) of methyl or trifluoromethyl, usually can side reaction generate the isomer Δ 2-cephem compounds (with reference to reference example 1) of a large amount of two keys.
Produce Δ 2-cephem compounds in order to suppress side reaction, must under extremely low temperature, react, or use this special organic bases of H ü nig alkali (diisopropylethylamine) to react.In addition, R
4During for p-methylphenyl, as Chemistry and Biology of β-LactamAntibiotics, 164 (1982) records like that, relatively the demulcent aromatic base---pyridine reacts to use alkalescence as organic bases, even still also just obtained the mixture of Δ 3-cephem compounds and Δ 2-cephem compounds under this occasion.
In addition, Pure ﹠amp; Appl.Chem., put down in writing the use dimethyl formamide as reaction solvent in 59,1041 (1987), with the methylsulfonyl reaction of the organic bases of above-mentioned same use pyridine etc.But the method for document record produces about 10% Δ 2-cephem compounds 0～5 ℃ of following side reaction, even also can side reaction produce about 4% Δ 2-cephem compounds (with reference to reference example 2 and 3) in addition near-30 ℃.
Side reaction produces Δ 2-cephem compounds and causes the purity and the yield of the active parent nucleus Δ 3-cephem compounds of cynnematin to reduce, and brings very big load to process for refining.Use the reaction of organic bases, all be dissolved in state the reaction solvent from just having reached at first alkali, because the isomerization of two keys is carried out in the reaction of leaving away of the C2 position hydrogen atom that alkali causes, side reaction generation Δ 2-cephem compounds easily.Therefore, the industrialization aspect of this reaction still leaves very big problem.
The object of the present invention is to provide a kind of problem that can avoid side reaction to produce Δ 2-cephem compounds, prepare easier, the preparation method that practicality is high of 3-sulfonyloxy-Δ 3-cephem compounds with high purity, high yield.
Disclosure of the Invention
The present invention relates to the preparation method of the 3-sulfonyloxy-3-cephem compounds of formula (3) expression, it is characterized in that, in organic solvent, in the presence of alkaline carbonate or alkaline earth metal carbonate, make the 3-hydroxyl-3-cephem compounds of formula (1) expression and the sulfonyl halogen compound reaction of formula (2) expression.
(in the formula, R
1Expression hydrogen atom, halogen atom, protected amino or group Ar-CH=N-(Ar represents to have substituent aryl sometimes).R
2Represent hydrogen atom, halogen atom, lower alkoxy, lower acyl, protected hydroxyl or have protected hydroxyl sometimes as substituent low alkyl group.R
3Expression hydrogen atom or carboxylic acid protecting group.〕
R
4SO
2X (2)
(in the formula, R
4Expression has substituent low alkyl group sometimes, or has substituent aryl sometimes.X represents halogen atom.)
(in the formula, R
1～R
4Same as described above.)
The inventor is when the preparation method of exploitation 3-sulfonyloxy-3-cephem compounds, found not adopt the organic bases that causes double-bond isomerization easily, use alkaline carbonate or this mineral alkali of alkaline earth metal carbonate, the reaction system of reacting under can industrialized mild reaction conditions, thus the present invention finished.
According to the present invention, can side reaction produce Δ 2-cephem compounds hardly, with the 3-sulfonyloxy-3-cephem compounds of high purity and high yield preparation formula (3) expression.
Each group that occurs in this specification sheets is specific as follows described.In addition, short of special explanation in this specification sheets, halogen atom is meant fluorine, chlorine, bromine, iodine, and low alkyl group is meant the alkyl of the carbonatoms 1～4 of straight or brancheds such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl.In addition, aryl is meant phenyl, naphthyl etc.
As R
1The protected amino of expression; remove Protective Groups in OrganicSynthesis; Theodora W.Greene work; outside the various groups of the 7th chapter of 1981 (being designated hereinafter simply as " document ") (the 218th～287 page) record; can also enumerate for example benzene acetamide oxide base; to the methylenedioxy phenoxy acetamido; to anisole acetamide oxide base; to chlorobenzene acetamide oxide base; to bromobenzene acetamide oxide base; the phenyl-acetamides base; the p-methylphenyl acetamido; the p-methoxyphenyl acetamido; the rubigan acetamido; to the bromophenyl acetamido; phenyl one chloracetyl amido; the phenyl-dichloroacetamide base; phenyl glycoloyl amido; phenyl acetoxyl group acetamido; alpha-oxo-phenyl-acetamides base; the thienyl acetamido; benzoylamino; to the toluyl amido; to the tert.-butylbenzene formamido-; to the methoxy benzamide base; to chloro-benzoyl amino; to the brombenzamide base; phenylglycinamide base or amino protected phenylglycinamide base; amidess such as a side or all protected p-hydroxybenzene glycyl of both sides amido in p-hydroxybenzene glycyl amido or amino and the hydroxyl, phthalimide-based; imines classes such as nitro phthalimide-based.The various groups of amino for example above-mentioned document the 7th chapter of protecting group (the 218th～287 page) record in phenylglycinamide base and the p-hydroxybenzene glycyl amido.In addition, the various groups of for example above-mentioned document the 2nd chapter of the protecting group of hydroxyl (the 10th～72 page) record in the p-hydroxybenzene glycyl amido.
R
2The lower alkoxy of expression is the alkoxyl group of straight or branched carbonatomss 1～4 such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy for example.
R
2The lower acyl of expression is the acyl group of straight or branched carbonatomss 1～4 such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl for example.
R
2Expression have hydroxyl or protected hydroxyl as protected hydroxyl and R in the substituent low alkyl group
2The group of for example above-mentioned document the 2nd chapter of protecting group (the 10th～72 page) record of the protected hydroxyl of expression.
R
2The above-mentioned replacement low alkyl group of expression can replace more than 1 on the identical or different carbon atom with the substituting group that is selected from the identical or different kind in hydroxyl or the above-mentioned protected hydroxyl.
R
3The carboxylic acid protecting group of expression removes the various groups that above-mentioned document the 5th chapter (the 152nd～192 page) puts down in writing, and for example can also enumerate allyl group, phenmethyl, to mehtoxybenzyl, p-nitrophenyl methyl, diphenyl methyl, trichloromethyl, three chloroethyls, the tertiary butyl etc.
Ar represents has substituent aryl and R sometimes
4Expression have the substituent kind that also can replace on substituent low alkyl group or the aryl for example halogen atom, nitro, cyano group, aryl, low alkyl group, single lower alkyl amino, two lower alkyl aminos, sulfydryl, radicals R sometimes
5S-(R
5Be low alkyl group or aryl) alkylthio or the arylthio, methanoyl, radicals R of expression
5COO-(R
5Same as described above) expression acyloxy, formyl radical, radicals R
5CO-(R
5Same as described above) expression acyl group, radicals R
5O-(R
5Same as described above) alkoxyl group or the aryloxy, carboxyl, radicals R of expression
5OCO-(R
5Same as described above) alkoxy carbonyl or the aryloxycarbonyl etc. of expression, R
4In low alkyl group or aryl can replace on the identical or different carbon atom more than 1 with the substituting group that is selected from above-mentioned substituent identical or different kind.
3-hydroxyl-3-the cephem compounds of formula (1) expression of using as raw material among the present invention can be according to for example Chem.Lett., the method preparation of 1867 (1990) records.
In the present invention, in the presence of alkaline carbonate or alkaline earth metal carbonate, make the 3-hydroxyl-3-cephem compounds of formula (1) expression and the sulfonyl halogen compound reaction of formula (2) expression, the 3-sulfonyloxy-3-cephem compounds of can preparation formula (3) representing.
The carbonate of basic metal or alkaline-earth metal is yellow soda ash, salt of wormwood, Quilonum Retard, magnesiumcarbonate, lime carbonate, barium carbonate, Strontium carbonate powder etc. for example.There is no particular limitation for the shape of these carbonate, can suitably select in wide scope such as powdery, bulk, more preferably uses the powdered material.The particle diameter of the carbonate of powdered basic metal or alkaline-earth metal can suitably be selected in wide scope, preferably uses 10～500 desired substances.The consumption of the carbonate of these basic metal or alkaline-earth metal is generally 0.1～50 times of molar weight with respect to the compound of formula (1), preferred 0.5～10 times of molar weight.
The sulfonyl halogen compound concrete example of formula (2) expression such as methylsulfonyl chloride, trifluoromethanesulfchloride chloride, Tosyl chloride etc. with respect to the compound of formula (1), are generally 0.1～50 times of molar weight, preferred 1～10 times of molar weight.
Reaction of the present invention is preferably at separately or in the mixed solvent of amide solvent or cyclic ether kind solvent, or carries out in the solvent that combines of these solvents and other organic solvent.Operable amide solvent or cyclic ether kind solvent be dimethyl formamide (DMF), diethylformamide, N,N-DIMETHYLACETAMIDE amidess such as (DMA) for example, N-Methyl pyrrolidone cyclic amides such as (NMP), ring-type ethers such as tetrahydrofuran (THF) (THF), dioxane, dioxolane.
In addition, the organic solvent that can be used in combination with above-mentioned solvent is methyl-formiate for example, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl propionate, low-grade alkyl carboxylic acids' such as ethyl propionate lower alkyl esters class, acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), ketones such as metacetone, Anaesthetie Ether, ethyl propyl ether, ethyl-butyl ether, dipropyl ether, Di Iso Propyl Ether, dibutyl ether, ethers such as glycol dimethyl ether, acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, nitriles such as valeronitrile, benzene, toluene, dimethylbenzene, chlorobenzene, replacement or unsubstituted aromatics classes such as methyl-phenoxide, methylene dichloride (MDC), chloroform, ethylene dichloride, trichloroethane, ethylene dibromide, propylene dichloride, tetracol phenixin, halogenated hydrocarbons such as freonll-11, pentane, hexane, heptane, hydro carbons such as octane, pentamethylene, hexanaphthene, suberane, cycloalkanes such as cyclooctane.
The combination of preferred solvent is DMF/THF, DMF/ ethyl acetate, DMF/MDC, DMF/ toluene, DMF/ acetone, DMF/ ether, DMF/ acetonitrile, THF/ acetone, THF/ acetonitrile, NMP/ toluene, NMP/MDC, NMP/ acetonitrile, DMA/ toluene, DMA/ acetone, DMA/ acetonitrile, DMA/MDC, DMF/ acetone/acetonitrile, DMF/MDC/ acetonitrile etc. for example.
The solvent that uses among the present invention can be adjusted, and carbonate necessary amount in reaction of above-mentioned basic metal or alkaline-earth metal is suitably dissolved supply response system.
Also can contain water in case of necessity in these organic solvents.These solvent phase use about 2～200L, about preferred 3～100L usually for the compound of 1kg formula (1).Be reflected at-50～100 ℃, carry out in preferred-35～40 ℃ the scope.
The compound of formula (3) finishes the back in reaction can obtain pure product substantially by carrying out the operation of conventional extracting operation or partial crystallization, can certainly adopt other method refining.
With the 3-hydroxyl-3-cephem compounds of formula (1) expression as raw material, in the presence of alkaline carbonate or alkaline earth metal carbonate, make it to react with sulfonyl halogen compound, can side reaction produce Δ 2-cephem compounds hardly, can be with the 3-sulfonyloxy-3-cephem compounds of high purity and high yield preparation formula (3) expression.
Compound according to the formula (3) of the present invention preparation can be according to for example Pure ﹠amp; Appl.Chem., the methods of 59,1041 (1987) records are derived and are obtained the oral antibiotic Ceftibuten.In addition; the compound of formula (3) also can be willing to that the method for flat 11-247272 number record derives and obtain 3-vinyl-3-cephem compounds according to the spy; through deprotection technology; method according to the public clear 63-20435 communique record of spy; can derive and obtain oral antibiotic Cefixime Micronized (Cefixime) (up-to-date antibiotics guide the 9th edition; wine well gram is controlled work; the 83rd page; 1994); also can derive and obtain Cefdinir (Cefdinir) (up-to-date antibiotics guide the 9th edition; wine well gram is controlled work, and the 86th page, 1994).
According to the present invention, the R of formula (1) compound
1, R
2And R
3Substituting group irrelevant with reaction owing to, can access formula (3) compound that the intermediate that can be used as useful non-natural type antimicrobial drug utilizes no matter its kind all can be reacted.
The preferred forms of invention
Describe the present invention in detail below in conjunction with embodiment and reference example, but the present invention is not subjected to any qualification of these embodiment.
Embodiment 1
Take by weighing the compound (R of formula (1)
1=phenyl-acetamides base, R
2=H, R
3=diphenyl methyl) (1a) 180g and yellow soda ash 70g add the N that is cooled to 3～5 ℃, and dinethylformamide (DMF) 600mL and methylsulfonyl chloride 52mL stirred 2 hours down at 3～5 ℃.Reaction solution is injected among methylene dichloride 2L and the water 2L, extraction, behind the organic layer that water 2L washing obtains, distillation removes and desolvates under reduced pressure.In the residue that obtains, add 75% methyl alcohol 2L and make it crystallization, 3～5 ℃ of following slakings after 1 hour, filter, drying, obtain the compound (R of formula (3)
1～R
3Same as described above, R
4=methyl) (3a) 195g.Yield: 94% (Δ 2-cephem compounds content: 0.2%)
1H NMR(300MHz，DMSO-d
6)δ3.17(s，3H)，3.48(d，J＝14Hz，1H)，3.56(d，J＝14Hz，1H)，3.74(d，J＝18Hz，1H)，4.00(d，J＝18Hz，1H)，5.26(d，J＝4.6Hz，1H)，5.82(dd，J＝4.6，8.2Hz，1H)，6.92(s，1H)，7.18-7.52(m，15H)，9.23(d，J＝8.2Hz，1H).
Reference example 1
Compound (1a) 90mg is dissolved among-5 ℃ the tetrahydrofuran (THF) 1mL, adds methylsulfonyl chloride 19 μ L and triethylamine 67 μ L, stirred 1 hour down at-5 ℃.With high performance liquid chromatography (HPLC) assaying reaction liquid.Adopt the external perimysium reference method to obtain the output of various products.As a result, under the residual state that compound (1a) 8% arranged, reaction solution is compound (3a) 30mg (26%) and the mixture of Δ 2-cephem compounds 71mg (61%).
Reference example 2
Compound (1a) 100mg is dissolved among 0～5 ℃ the DMF 1mL, adds methylsulfonyl chloride 21 μ L and triethylamine 74 μ L, stirred 1 hour down at 0～5 ℃.With HPLC assaying reaction liquid, the result obtains the mixture of compound (3a) 91mg (82%) and Δ 2-cephem compounds 11mg (10%).
Reference example 3
Change into-30 ℃ except temperature and the temperature of reaction of the DMF that will add, carry out equally with reference example 2.With HPLC assaying reaction liquid, the result obtains the mixture of compound (3a) 98mg (88%) and Δ 2-cephem compounds 4mg (4%).
Embodiment 2
Take by weighing the compound (R of formula (1)
1=phenyl-acetamides base, R
2=H, R
3=to mehtoxybenzyl) (1b) 100mg and yellow soda ash 43mg, add the DMF 0.4mL and the methylsulfonyl chloride 32 μ L that are cooled to 3～5 ℃, stirred 2 hours down at 3～5 ℃.Reaction solution is injected among methylene dichloride 20mL and the water 20mL, extraction, the organic layer that water 20mL washing obtains, after drying on the sal epsom, underpressure distillation removes and desolvates.With the refining residue that obtains of column chromatography, obtain the compound (R of formula (3)
1～R
3Same as described above, R
4=methyl) (3b) 122mg.The part that does not have Δ 2-cephem compounds when separating in addition, with column chromatography.Yield: 96%
1H NMR(300MHz，CDCl
3)δ3.05(s，3H)，3.55(d，J＝18Hz，1H)，3.59(d，J＝16Hz，1H)，3.66(d，J＝16Hz，1H)，3.77(d，J＝18Hz，1H)，3.79(s，3H)，4.98(d，J＝4.9Hz，1H)，5.16(d，J＝12Hz，1H)，5.22(d，J＝12Hz，1H)，5.83(dd，J＝4.9，9.1Hz，1H)，6.20(d，J＝9.1Hz，1H)，6.82-7.40(m，9H).
Embodiment 3～8
Reaction solvent is changed over following solvent, react similarly to Example 2, obtain compound (3b).The result is as shown in table 1.The generation ratio of Δ 2-cephem compounds is below 0.3% among each embodiment.
[table 1]
| Embodiment | Solvent | Yield (%) |
| 3 | NMP | 92 |
| 4 | DMA | 90 |
| 5 | THF | 85 |
| 6 | MDC/DMF | 85 |
| 7 | Ethyl acetate/DMF | 82 |
| 8 | THF/DMF | 85 |
Embodiment 9～13
Yellow soda ash is changed over following alkaline carbonate or alkaline earth metal carbonate, react similarly to Example 2, obtain compound (3b).The result is as shown in table 2.The generation ratio of Δ 2-cephem compounds is below 0.4% among each embodiment.
[table 2]
| Embodiment | Alkaline carbonate/alkaline earth metal carbonate | Yield (%) |
| 9 | Salt of wormwood | 94 |
| 10 | Quilonum Retard | 92 |
| 11 | Lime carbonate | 84 |
| 12 | Strontium carbonate powder | 82 |
| 13 | Barium carbonate | 82 |
Embodiment 14
Take by weighing compound (1a) 1g and yellow soda ash 360mg, add the DMF10mL and the Tosyl chloride 648mg that are cooled to 3～5 ℃, stirred 2 hours down at 3～5 ℃.Below, carry out aftertreatment similarly to Example 2, obtain the compound (R of formula (3)
1=phenyl-acetamides base, R
2=H, R
3=diphenyl methyl, R
4=p-methylphenyl) (3c) 1.26g.Confirm not have the part of Δ 2-cephem compounds when separating in addition, with column chromatography.Yield: 96%
1H NMR(300MHz，CDCl
3)δ2.37(s，3H)，3.42(d，J＝18Hz，1H)，3.58(d，J＝16Hz，1H)，3.65(d，J＝16Hz，1H)，3.77(d，J＝18Hz，1H)，4.99(d，J＝4.8Hz，1H)，5.81(dd，J＝4.8，8.7Hz，1H)，6.05(d，J＝8.7Hz，1H)，6.77(s，1H)，7.15-7.49(m，19H).
Embodiment 15
Take by weighing compound (1b) 1g and yellow soda ash 367mg, add the DMF 10mL and the Tosyl chloride 715mg that are cooled to 3～5 ℃, stirred 2 hours down at 3～5 ℃.Below, carry out aftertreatment similarly to Example 2, obtain the compound (R of formula (3)
1=phenyl-acetamides base, R
2=H, R
3=to mehtoxybenzyl, R
4=p-methylphenyl) (3d) 1.27g.Confirm not have the part of Δ 2-cephem compounds when separating in addition, with column chromatography.Yield: 95%
1H NMR(300MHz，CDCl
3)δ2.45(s，3H)，3.34(d，J＝19Hz，1H)，3.57(d，J＝16Hz，1H)，3.62(d，J＝19Hz，1H)，3.64(d，J＝16Hz，1H)，3.80(s，3H)，4.94(d，J＝4.8Hz，1H)，4.98(d，J＝12Hz，1H)，5.03(d，J＝12Hz，1H)，5.79(dd，J＝4.8，9.0Hz，1H)，6.17(d，J＝9.0Hz，1H)，6.85-7.75(m，13H).
Embodiment 16
Take by weighing compound (1a) 300mg and yellow soda ash 108mg, add the DMF 3mL and the trifluoromethanesulfchloride chloride 0.12mL that are cooled to 3～5 ℃, stirred 2 hours down at 3～5 ℃.Below, carry out aftertreatment similarly to Example 2, obtain the compound (R of formula (3)
1=phenyl-acetamides base, R
2=H, R
3=diphenyl methyl, R
4=trifluoromethyl) (3e) 349mg.Confirm not have the part of Δ 2-cephem compounds when separating in addition, with column chromatography.Yield: 92%
1H NMR(300MHz，DMSO-d
6)δ3.50(d，J＝14Hz，1H)，3.58(d，J＝14Hz，1H)，3.82(d，J＝18Hz，1H)，4.03(d，J＝18Hz，1H)，5.32(d，J＝4.8Hz，1H)，5.90(dd，J＝8.1Hz，1H)，6.94(s，1H)，7.20-7.54(m，15H)，9.26(d，J＝8.1Hz，1H).
Embodiment 17
Take by weighing compound (1b) 300mg and yellow soda ash 119mg, add the DMF 3mL and the trifluoromethanesulfchloride chloride 0.13mL that are cooled to 3～5 ℃, stirred 2 hours down at 3～5 ℃.Below, carry out aftertreatment similarly to Example 2, obtain the compound (R of formula (3)
1=phenyl-acetamides base, R
2=H, R
3=to mehtoxybenzyl, R
4=trifluoromethyl) (3f) 348mg.Confirm not have the part of Δ 2-cephem compounds when separating in addition, with column chromatography.Yield: 90%
1H NMR(300MHz，DMSO-d
6)δ3.36(d，J＝18Hz，1H)，3.57(d，J＝16Hz，1H)，3.65(d，J＝16Hz，1H)，3.69(d，J＝18Hz，1H)，3.79(s，3H)，4.98(d，J＝4.6Hz，1H)，5.14(d，J＝12Hz，1H)，5.33(d，J＝12Hz，1H)，5.85(dd，J＝4.6，8.6Hz，1H)，6.19(d，J＝8.6Hz，1H)，6.83-7.40(m，9H).
Embodiment 18～22
Temperature of reaction is changed over following temperature, react similarly to Example 2, obtain compound (3b).The result is as shown in table 3.The generation ratio of Δ 2-cephem compounds is below 0.5% among each embodiment.
[table 1]
| Embodiment | Temperature (℃) | Yield (%) | The content (%) of Δ 2-cephem compounds |
| 18 | -30～-25 | 93 | 0.1 |
| 19 | -10～-5 | 92 | 0.1 |
| 20 | 10～15 | 90 | 0.3 |
| 21 | 25～30 | 87 | 0.3 |
| 22 | 40～45 | 72 | 0.5 |
Embodiment 23
Take by weighing the compound (R of formula (1)
1=p-CH
3O-C
6H
4-CH=N-, R
2=H, R
3=diphenyl methyl) (1c) 300mg and yellow soda ash 117mg add the DMF 3mL and the methylsulfonyl chloride 0.09mL that are cooled to 3～5 ℃, stir 2 hours down at 3～5 ℃.Below, carry out aftertreatment similarly to Example 2, obtain compound (3g) 318mg of formula (3).Yield: 92% (Δ 2-cephem compounds content: 0.2%)
1H NMR(300MHz，CDCl
3)δ2.72(s，3H)，2.56(d，J＝18Hz，1H)，3.81(s，3H)，3.85(d，J＝18Hz，1H)，5.16(d，J＝4.8Hz，1H)，5.34(d，J＝4.8Hz，1H)，6.88-7.76(m，14H)，6.98(s，1H)，8.46(s，1H).
In addition, the expansion solvent of the column chromatography of using among the embodiment 2～22 is benzene: hexane=4: 1～6: 1.
Reference example 4 (by the synthetic Ceftibuten of compound (3a))
The compound that embodiment 1 obtains (3a) can be according to Pure ﹠amp; Appl.Chem., the methods of 59,1041 (1987) records are derived and are obtained Ceftibuten.
Make compound (3a) in dichloromethane solvent with phosphorus pentachloride/pyridine reagent react after, reaction solution is cooled to-35 ℃, handle with methyl alcohol, obtain 7-amino-3-mesyloxy cephem hydrochloride (4).In acetic acid, compound (4) is reduced, obtain 7-amino-3-cephem hydrochloride (5), in the presence of alkali, make it and acyl chlorides (6) reaction, obtain precursor (7) with the zinc reaction.Precursor (7) is through final deprotection reaction, and can derive obtains Ceftibuten.
Ceftibuten
[in the formula, Ph represents phenyl, and Z represents benzoyl, and PRN represents group-CH
2CH=C (CH
3)
2]
Reference example 5 (by the synthetic Cefixime Micronized of compound (3a))
The compound that embodiment 1 obtains (3a) is willing to the method for flat 11-247272 number record according to the spy, derive and obtain 3-vinyl-3-cephem compounds (8), make it in dichloromethane solvent with phosphorus pentachloride/pyridine reagent react after, reaction solution is cooled to-35 ℃, handle with methyl alcohol, generate 7-amino-3-vinyl-3-cephem hydrochloride (9).In compound (9), add phenol, reacted 1 hour down, obtain 7-amino-3-vinyl-3-cephem-4-formic acid (10) at 45 ℃.Compound (10) passes through and the reaction of 7 side chains, final deprotection reaction according to the method for the public clear 63-20435 of spy number record, and can derive obtains Cefixime Micronized.
(10) Cefixime Micronized
Industrial applicibility
According to the present invention, can side reaction produce Δ 2-cephem compounds hardly, can prepare with high-purity and high yield the intermediate 3-sulfonyloxy-3-cephem compounds of the wide anti-mattress medicine of effective non-natural type of anti-mattress spectrum.
Claims (3)
1. the preparation method of the 3-sulfonyloxy-3-cephem compounds of formula (3) expression,
It is characterized in that, in organic solvent, in the presence of alkaline carbonate or alkaline earth metal carbonate, make the 3-hydroxyl-3-cephem compounds of formula (1) expression and the sulfonyl halogen compound reaction of formula (2) expression,
R
4SO
2X (2)
In the formula (1), R
1Expression hydrogen atom, halogen atom, protected amino or group Ar-CH=N-, Ar represents to have substituent aryl, R
2Represent hydrogen atom, halogen atom, lower alkoxy, lower acyl, protected hydroxyl or have protected hydroxyl sometimes as substituent low alkyl group, R
3Expression hydrogen atom or carboxylic acid protecting group;
In the formula (2), R
4Optional low alkyl group or the optional aryl that is replaced by low alkyl group that is replaced by halogen atom of expression, X represents halogen atom;
In the formula (3), R
1～R
4Same as described above;
Wherein, the described substituting group that can have substituent aryl is selected from halogen atom, nitro, cyano group, aryl, low alkyl group, single lower alkyl amino, two lower alkyl aminos, sulfydryl, radicals R
5Alkylthio that S-represents or arylthio, methanoyl, radicals R
5The acyloxy that COO-represents, formyl radical, radicals R
5The acyl group that CO-represents, radicals R
5Alkoxyl group that O-represents or aryloxy, carboxyl, radicals R
5The alkoxy carbonyl that OCO-represents or the group of aryloxycarbonyl, wherein R
5Be low alkyl group or aryl;
The above low alkyl group, lower alkoxy, lower acyl, single lower alkyl amino, two lower alkyl aminos have 1～4 carbon atom, and aryl refers to phenyl or naphthyl;
Described organic solvent is at least a kind that is selected from amide solvent and the cyclic ether kind solvent.
2. preparation method as claimed in claim 1, sulfonyl halogen compound (2) is methylsulfonyl chloride, trifluoromethanesulfchloride chloride, Tosyl chloride.
3. preparation method as claimed in claim 1, alkaline carbonate or alkaline earth metal carbonate are yellow soda ash, salt of wormwood, Quilonum Retard, magnesiumcarbonate, lime carbonate, barium carbonate, Strontium carbonate powder.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26615899A JP4535530B2 (en) | 1999-09-20 | 1999-09-20 | Method for producing 3-sulfonyloxy-3-cephem compound |
| JP266158/1999 | 1999-09-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1322207A CN1322207A (en) | 2001-11-14 |
| CN1220693C true CN1220693C (en) | 2005-09-28 |
Family
ID=17427101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008020035A Expired - Fee Related CN1220693C (en) | 1999-09-20 | 2000-09-07 | Process for preparation of 3-sulfonyloxy-3-cephem compounds |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1132391B1 (en) |
| JP (1) | JP4535530B2 (en) |
| KR (1) | KR100439491B1 (en) |
| CN (1) | CN1220693C (en) |
| AT (1) | ATE345346T1 (en) |
| ES (1) | ES2274802T3 (en) |
| WO (1) | WO2001021622A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397455A (en) * | 2016-08-30 | 2017-02-15 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infective drug ceftibuten crystal compound and composition thereof |
| CN108659009A (en) * | 2018-07-19 | 2018-10-16 | 广东立国制药有限公司 | A kind of process for purification of high-purity Ceftibuten |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010097714A (en) * | 2000-04-25 | 2001-11-08 | 박종덕 | service system for washing and method thereof |
| EP2912184B1 (en) | 2012-10-25 | 2017-01-18 | Scientist of Fortune S.A. | Production of alkenes from 3-hydroxy-1-carboxylic acids via 3-sulfonyloxy-1-carboxylic acids |
| CN102977124B (en) * | 2012-12-13 | 2014-11-26 | 山东诚创医药技术开发有限公司 | Preparation method of 7beta-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine onium)-2-thiothiazole]-3-cephem-4-benzhydryl carboxylate |
| CN104910185B (en) * | 2015-03-10 | 2018-02-16 | 国药集团致君（苏州）制药有限公司 | A kind of preparation method of Ceftaroline Fosamil intermediate parent nucleus |
| CN109096303A (en) * | 2018-09-11 | 2018-12-28 | 南通康鑫药业有限公司 | A kind of synthetic method of Ceftibuten |
| CN114702511B (en) * | 2022-04-21 | 2023-07-25 | 湖北凌晟药业股份有限公司 | Preparation method of trans-isomer of ceftibuten |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH605997A5 (en) * | 1974-08-30 | 1978-10-13 | Ciba Geigy Ag | |
| JPS54100392A (en) * | 1978-01-24 | 1979-08-08 | Sankyo Co Ltd | Production of cephalosporin derivative |
| FR2550200B1 (en) * | 1983-08-01 | 1988-04-08 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS WITH ANTIMICROBIAL ACTIVITY AND NOVEL PRODUCTS THUS OBTAINED |
| GB8326332D0 (en) * | 1983-09-30 | 1983-11-02 | Fujisawa Pharmaceutical Co | Preparation of cephem ester compounds |
| GB8416651D0 (en) * | 1984-06-29 | 1984-08-01 | Erba Farmitalia | Penem derivatives |
| US4870168A (en) * | 1987-02-26 | 1989-09-26 | Bristol-Myers Company | 3-Unsaturated alkyl cephems from 3-triflyl cephems |
| US5455239A (en) * | 1993-08-05 | 1995-10-03 | Merck & Co. Inc. | 3-aryl of heteroaryl-7-heteroaralkylamido cephalosporin compounds, compositions and methods of use |
| JPH0761987A (en) * | 1993-08-24 | 1995-03-07 | Takeda Chem Ind Ltd | Cephem compound, its production and antibacterial composition |
| US5498777A (en) * | 1994-07-20 | 1996-03-12 | Merck & Co., Inc. | 3-thioheteroaryl cephalosporin compounds, compositions and methods of use |
-
1999
- 1999-09-20 JP JP26615899A patent/JP4535530B2/en not_active Expired - Fee Related
-
2000
- 2000-09-07 ES ES00956989T patent/ES2274802T3/en not_active Expired - Lifetime
- 2000-09-07 CN CNB008020035A patent/CN1220693C/en not_active Expired - Fee Related
- 2000-09-07 KR KR10-2001-7006335A patent/KR100439491B1/en not_active IP Right Cessation
- 2000-09-07 EP EP00956989A patent/EP1132391B1/en not_active Expired - Lifetime
- 2000-09-07 AT AT00956989T patent/ATE345346T1/en active
- 2000-09-07 WO PCT/JP2000/006079 patent/WO2001021622A1/en active IP Right Grant
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397455A (en) * | 2016-08-30 | 2017-02-15 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infective drug ceftibuten crystal compound and composition thereof |
| CN108659009A (en) * | 2018-07-19 | 2018-10-16 | 广东立国制药有限公司 | A kind of process for purification of high-purity Ceftibuten |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1132391A4 (en) | 2002-06-12 |
| JP2001089483A (en) | 2001-04-03 |
| JP4535530B2 (en) | 2010-09-01 |
| EP1132391B1 (en) | 2006-11-15 |
| KR100439491B1 (en) | 2004-07-14 |
| EP1132391A1 (en) | 2001-09-12 |
| ATE345346T1 (en) | 2006-12-15 |
| CN1322207A (en) | 2001-11-14 |
| KR20010075725A (en) | 2001-08-09 |
| WO2001021622A1 (en) | 2001-03-29 |
| ES2274802T3 (en) | 2007-06-01 |
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